The synthesis and transformations of 2-[2-ethoxycarbonyl-2-(2-pyridinyl)ethenyl]amino-3-dimethylaminopropenoates. The synthesis of substituted β-amino-α,β-didehydro-α-amino acid derivatives

Article abstract of DOI:10.1002/jhet.5570380409

Alkyl (Z)-2-[(E)-2-ethoxycarbonyl-2-(2-pyridinyl)ethenyl] amino-3-dimethylaminopropenoates 7 and 8 were prepared from ethyl 2-pyridinylacetate (1) in two steps. Substitution of the dimethylamino group with alkyl-, aryl-, or heteroarylamines afforded the corresponding β-alkyl- 22-24, β-aryl- 25-35, and β-herteroaryl-amino-α,β-didehydro-α-amino acid 36 and 37 derivatives, intermediates for further preparation of various heterocyclic systems. The orientation around both double bonds were determined by various nmr techniques.

Full text of DOI:10.1002/jhet.5570380409

Jul-Aug 2001
The Synthesis and Transformations of 2-[2-Ethoxycarbonyl-2-(2-
pyridinyl)ethenyl]amino-3-dimethylaminopropenoates. The Synthesis
of Substituted β-Amino-α,β-didehydro-α-amino Acid Derivatives
859
Lucija Jukic´ [a], Simon Recˇnik [a], Simona Golicˇ Grdadolnik [b],
Jurij Svete* [a], Branko Stanovnik* [a]
[a] Faculty of Chemistry and Chemical Technology, University of Ljubljana, Asˇkercˇeva 5, 1000 Ljubljana, Slovenia
[b] L01, Department of NMR and Molecular Modelling, National Institute of Chemistry,
Hajdrihova 19, POB 3440, 1000 Ljubljana, Slovenia
Received December 15, 2000
Alkyl (Z)-2-[(E)-2-ethoxycarbonyl-2-(2-pyridinyl)ethenyl]amino-3-dimethylaminopropenoates 7 and 8
were prepared from ethyl 2-pyridinylacetate (1) in two steps. Substitution of the dimethylamino group with
alkyl-, aryl-, or heteroarylamines afforded the corresponding β-alkyl- 22-24, β-aryl- 25-35, and β-herteroaryl-
amino-α,β-didehydro-α-amino acid 36 and 37 derivatives, intermediates for further preparation of various
heterocyclic systems. The orientation around both double bonds were determined by various nmr techniques.
J. Heterocyclic Chem., 38, 859 (2001).
Recently, substituted 2-acylamino- or 2-hydroxy-3-
(heteroaryl)lactic acid derivatives, as well as for the prepa-
ration of heterocyclic systems with an α-amino acid struc-
tural element incorporated into the cyclic system [17-23].
In continuation of our studies in this area, we report the
synthesis of alkyl (Z)-2-[(E)-2-alkoxycarbonyl-2-(2-
pyridinyl)ethenyl]amino-3-dimethylaminopropenoates 7 and
8, and their further transformations with alkyl-, aryl-, and
heteroarylamines into β-alkyl (aryl and heteroaryl)amino-
α,β-didehydro-α-amino acid derivatives 22-37 as intermedi-
ates for preparation of various heterocyclic systems.
Alkyl (E)-N-[2-ethoxycarbonyl-2-(2-pyridinyl)ethenyl)-
glycinates 5 and 6 were prepared by heating a mixture of
ethyl 2-pyridinylacetate (1) and N,N-dimethylformamid
dimethylacetal (DMFDMA) or (t-butyloxy)bis(dimethyl-
amino)methane (Bredereck's reagent) at 85 °C for 1.5 hours
in an argon atmosphere to give ethyl 3-(dimethylamino-2-
(2-pyridinyl)propenoate (2) followed, without purification,
by treatment with an alkyl glycinate hydrochloride 3, 4 in
ethanol by heating at reflux temperature for 1.5 hours in 80-
86% yield. They were transformed with (t-butyloxy)-
(dimethylamino)propenoates as masked α-formyl-α-
amino- or α-formyl-α-hydroxy acid derivatives, and
2-[(2,2-disubstituted ethenyl)amino]-3-(dimethylamino)-
propenoates and related compounds have been prepared in
our laboratory and used as reagents for preparation of var-
ious heterocyclic systems, such as 2H-pyran-2-ones and
fused pyran-2-ones, fused pyridinones, pyrimidinones [1-
10], imidazole-4-carboxylates [11], alkyl 1-acyl-3,4-disub-
stituted pyrrole-2-carboxylates [12,13], dialkyl 3-amino-
pyrrole-2,4-dicarboxylates and 5H-pyrrolo[3,2-d]-
pyrimidine derivatives [14], and (Z)-aplysinopsin analogs
in a simple and stereoselektive manner [15]. Alkyl 2-[2-
cyano-2-(2-pyridinyl)ethenyl]amino-3-dimethylamino-
propenoates have been transformed into alkyl 2-[2-cyano-
2-(2-pyridinyl)ethenyl]amino-3-[2-methoxycarbonyl-4-
(2-pyridinyl)-1H-pyrrol-3-yl]aminopropenoates [16].
Chiral 3-(dimethylamino)propenoate analogs derived from
L-glutamic and L-pyroglutamic acid have been used for
the preparation of (S)-3-(heteroaryl)alanine and (S)-3-
Scheme 1

860
L. Jukic´, S. Recˇnik, S. Golicˇ Grdadolnik, J. Svete, B. Stanovnik
Vol. 38
bis(dimethylamino)methane (Bredereck's reagent) in dry
toluene by heating under reflux for several hours into alkyl
(Z)-2-[(E)-2-ethoxycarbonyl-2-(2-pyridinyl)ethenyl]-
amino-3-dimethylamino-propenoates 7 and 8 in 91% and
62% yield, respectively. (Scheme 1).
The dimethylamino group in compounds 7 and 8 can be
easily substituted with benzyl amines 9-11, aromatic
amines 12-20, and heteroaromatic amines, such as
2-amino-5-chloropyridine (21) in acetic acid at room tem-
perature to form β-alkylamino-α,β-didehydro-α-amino
acid derivatives 22-24 in 15-43% yield, β-arylamino-α,β-
didehydro-α-amino acid derivatives 25-35 in 13-78%
yield, and β-heteroarylamino-α,β-didehydro-α-amino acid
derivatives 36 and 37 in 62 and 73% yield, respectively.
(Scheme 2). Experimental and analytical data are given in
Tables 1, 2, 3, and 4.
Structure Determination.
The structures of the new compounds were determined by
H nmr spectra and Heteronuclear Multiple Bond Correlation
1

Jul-Aug 2001
The Synthesis and Transformations of 2-[2-Ethoxycarbonyl-2-(2-
pyridinyl)ethenyl]amino-3-dimethylaminopropenoates
861
Table 1
Experimental and Analytical Data
o
Compound
Yield
(%)
mp ( C)
Molecular formula Analyses
Number of
isomers (ratio)
5
6
86
80
91
62
36
43
15
23
17
78
60
66
53
13
31
45
67
37
62
73
95-97
C
H
N O
2 4
1
1
13 16
from ethyl acetate/n-heptane (1:6)
Calcd: C, 59.08; H, 6.10; N, 10.60
Found: C, 58.85; H, 5.86; N, 10.40
57-61
C H N O
14 18 2 4-
from ethyl acetate/n-heptane (1:6)
Calcd: C, 60.42; H, 6.52; N, 10.07
Found:C, 60.43; H, 6.72; N, 10.00
7
115-117
C
H
N O
1
16 21
3 4
from ethyl acetate/n-heptane (1:3)
Calcd: C, 60.18; H, 6.63; N, 13.16
Found:C, 60.11; H, 6.88; N, 13.05
8
63-69
C
H
N O
1
17 23
3 4
from ethyl acetate/n-heptane (1:3)
Calcd: C, 61.25; H, 6.95; N, 12.60
Found:C, 61.23; H, 7.23; N, 12.57
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
106-108
from ethanol/water
C
H
N O
1 [a]
1 [a]
1 [a]
21 23
3 4
Calcd: C, 66.13; H, 6.08; N, 11.02
Found:C, 66.31; H, 6.17; N, 10.98
C H N O
Calcd: C, 64.22; H, 6.12; N, 10.21
Found:C, 64.43; H, 6.24; N, 10.23
C H N O
Calcd: C, 59.99; H, 5.49; N, 12.72
Found:C, 59.63; H, 5.82; N, 11.80
105-108
from ethanol/water
22 25 3 5
103-107
from acetone
22 24 4 6
132-144
from methanol
C
H
N O
4 [b]
(11:9:2:1)
20 21
3 4
Calcd: C, 65.38; H, 5.76; N, 11.44
Found:C, 65.31; H, 5.96; N, 11.43
128-130
from methanol
C
H
N O
1 [a]
21 23
3 5
Calcd: C, 63.47; H, 5.83; N, 10.57
Found:C, 63.75; H, 5.90; N, 10.55
129-155
from methanol
C
H
N O
4 [b, c]
21 23
3 5
Calcd: C, 63.47; H, 5.83; N, 10.57
Found:C, 63.54; H, 6.09; N, 10.49
163-178
from methanol/toluene
C
H
FN O
4 [b]
(11:6:1:1)
20 20
3 4
Calcd: C, 62.33; H, 5.23; N, 10.90
Found:C, 62.60; H, 5.33; N, 10.96
144-169
from methanol
C
H
ClFN O
4 [b]
(13:9:2:1)
20 19
3 4
Calcd: C, 57.22; H, 4.56; N, 10.01
Found:C, 57.25; H, 4.64; N, 10.02
156-162
from methanol
C
H
BrN O
2 [d]
(6:1)
20 20
3 4
Calcd: C, 53.82; H, 4.52; N, 9.42
Found:C, 53.75; H, 4.48; N, 9.37
129-132
from methanol/toluene
C
H
BrN O
2 [d]
(7:1)
20 20
3 4
Calcd: C, 53.82; H, 4.52; N, 9.42
Found:C, 54.37; H, 4.56; N, 9.42
138-160
from methanol
C
H
N O
2 [d]
(10:1)
20 20
4 6
Calcd: C, 58.25; H, 4.89; N, 13.58
Found:C, 58.01; H, 4.87; N, 13.52
158-162
from methanol
C
H
N O
2 [d]
(8:1)
20 20
4 6
Calcd: C, 58.25; H, 4.89; N, 13.58
Found:C, 58.19; H, 4.86; N, 13.59
121-135
from ethanol
C
H
N O
2 [c, d]
1 [a]
22 25
3 5
Calcd: C, 64.22; H, 6.12; N, 10.21
Found:C, 64.20; H, 6.22; N, 10.34
159-165
from ethanol
C H ClFN O
21 21 3 4
Calcd: C, 58.14; H, 4.88; N, 9.68
Found:C, 58.07; H, 5.01; N, 9.54
192-194
from ethanol
C
H
ClN O
1 [a]
19 19
4 4
Calcd: C, 56.65; H, 4.75; N, 13.91
Found:C, 56.67; H, 4.72; N, 13.97
193-196
C
H
ClN O
1 [a]
20 21
4 4
from ethanol/water
Calcd: C, 57.63; H, 5.08; N, 13.44
Found:C, 57.77; H, 5.10; N, 13.55
[a] (2E, 2'E). [b] (2E, 2'E) : (2Z, 2'E) : (2Z, 2'Z) : (2E, 2'Z). [c] The ratio was not determined. [d] (2E, 2'E) : (2Z, 2'E).

862
L. Jukic´, S. Recˇnik, S. Golicˇ Grdadolnik, J. Svete, B. Stanovnik
Vol. 38
Table 2
1
H nmr Data
Compound MHz
Solvent
δ (tetramethylsilane)
5
6
7
300
CDCl
1.33 (3H, t, COOCH CH ), 3.79 (3H, s, COOMe), 4.12 (2H, d, CH ), 4.24 (2H, q, COOCH CH ), 6.97 (1H, ddd, H ),
2 3 2 2 3 5
7.62 (1H, ddd, H ), 7.92 (1H, d, CHNH), 8.31 (1H, ddd, H ), 8.42 (1H, ddd, H ), 11.02 (1H, br.s, CHNH), J
= 8.5 Hz,
3
3
3
4
3
6
H3H4
J
= 1.1 Hz, J
= 1.0 Hz, J
= 7.4 Hz, J
= 2.0 Hz, J
= 5.0 Hz, J
= 12.8 Hz, J
= 6.0 Hz, J
=
H3H5
H3H6
H4H5
H4H6
H5H6
CHNH
CH2NH
CH2CH3
7.1 Hz.
1.30 (3H, t, COOCH CH ), 1.33 (3H, t, COOCH CH ), 4.10 (2H, d, CH ), 4.24 (2H, q, COOCH CH ), 4.25 (2H, q,
300
CDCl
2
3
2
3
2
2
3
COOCH CH ), 6.96 (1H, ddd, H ), 7.61 (1H, ddd, H ), 7.93 (1H, d, CHNH), 8.31 (1H, ddd, H ), 8.41 (1H, ddd, H ),
2
3
5
4
3
6
11.02 (1H, br.s, CHNH), J
= 8.5 Hz, J
= 1.1 Hz, J
= 1.0 Hz, J
= 7.4 Hz, J
= 2.0 Hz, J
= 5.0 Hz,
H3H4
H3H5
H3H6
H4H5
H4H6
H5H6
J
= 12.4 Hz, J
= 6.0 Hz, J
= 7.1 Hz.
CHNH
CH2NH
CH2CH3
300
CDCl
1.32 (3H, t, COOCH CH ), 3.03 (6H, s, CHNMe ), 3.71 (3H, s, COOMe), 4.23 (2H, q, COOCH CH ), 6.94 (1H, ddd, H ),
2
3
2
2
3
5
7.27 (1H, s, CHNMe ), 7.60 (1H, ddd, H ), 7.90 (1H, d, CHNH), 8.34-8.38 (2H, m, H H ), 11.52 (1H, br.s, CHNH),
2
4
3,
6
J
= 8.6 Hz, J
= 1.1 Hz, J
= 0.7 Hz, J
= 7.2 Hz, J
= 1.7 Hz, J
= 5.0 Hz, J
= 12.5 Hz, J
=
=
H3H4
H3H5
H3H6
H4H5
H4H6
H5H6
CHNH
CH2CH3
7.1 Hz.
DMSO-d 1.24 (3H, t, COOCH CH ), 3.00 (6H, s, CHNMe ), 3.59 (3H, s, COOMe), 4.14 (2H, q, COOCH CH ), 7.07 (1H, ddd, H ),
6
2
3
2
2
3
5
7.30 (1H, s, CHNMe ), 7.71 (1H, ddd, H ), 7.77 (1H, d, CHNH), 8.28 (1H, d, H ), 8.46 (1H, ddd, H ), 11.40 (1H, d, CHNH),
2
4
3
6
J
= 8.4 Hz, J
= 1.1 Hz, J
= 1.0 Hz, J
= 7.3 Hz, J
= 1.9 Hz, J
= 5.0 Hz, J
= 13.0 Hz, J
H3H4
H3H5
H3H6
H4H5
H4H6
H5H6
CHNH CH2CH3
7.0 Hz.
1.26 (3H, t, COOCH CH ), 1.31 (3H, t, COOCH CH ), 3.03 (6H, s, CHNMe ), 4.18 (2H, q, COOCH CH ), 4.25 (2H, q,
8
300
2
3
2
3
2
2
3
CDCl
COOCH CH ), 6.94 (1H, ddd, H ), 7.24 (1H, s, CHNMe ), 7.60 (1H, ddd, H ), 7.93 (1H, d, CHNH), 8.36 (1H, ddd, H ), 8.37
3
3
3
3
2
3
5
2
4
3
(1H, ddd, H ), 11.58 (1H, d, CHNH), J
= 8.5 Hz, J
= 1.1 Hz, J
= 1.0 Hz, J
= 7.4 Hz, J
= 1.9 Hz, J
=
6
H3H4
H3H5
H3H6
H4H5
H4H6
H5H6
4.6 Hz, J
= 12.6 Hz, J
= 7.1 Hz.
CHNH
CH2CH3
22
23
24
300
CDCl
(2E, 2'E): 1.30 (3H, t, COOCH CH ), 3.72 (3H, s, COOMe), 4.22 (2H, q, COOCH CH ), 4.40 (2H, d, R CH NHCH), 5.09
2 3 2 3 1 2
(1H, m, R CH NHCH), 6.94-6.97 (1H, m, H '), 7.26-7.39 (5H, m, 5H(Ph)), 7.44 (1H, d, R CH NHCH), 7.59-7.64 (1H, m,
1
2
5
1
2
H '), 7.95 (1H, d, CHNH), 8.30-8.41 (2H, m, H ', H '), 11.27 (1H, br.s, CHNH), J
= 5.6 Hz, J = 13.8 Hz,
4
3
6
R1CH2NHCH
R1CH2NHCH
J
= 9.0 Hz, J
= 7.2 Hz.
CHNH
CH2CH3
300
CDCl
(2E, 2'E): 1.30 (3H, t, COOCH CH ), 3.72, 3.80 (2x 3H, 2x s, COOMe, OMe), 4.22 (2H, q, COOCH CH ), 4.33 (2H, d,
2
3
2
3
R CH NHCH), 5.03 (1H, br.s, R CH NHCH), 6.89 (2H, d, H , H ), 6.95 (1H, dd, H '), 7.19 (2H, d, H , H ), 7.44 (1H, d,
1 2 1 2 3 5 5 2 6
R CH NHCH), 7.62 (1H, dd, H '), 7.93 (1H, br.s, CHNH), 8.31 (1H, d, H '), 8.37 (1H, d, H '), 11.28 (1H, br.s, CHNH),
1
2
4
3
6
J
= 8.8 Hz, J
= 6.6 Hz, J
= J
= 8.3 Hz, J
= 4.9 Hz, J
= 13.9 Hz, J
= 7.2 Hz.
H3'H4'
H4'H5'
H2H3
H5H6
R1CH2NHCH
R1CH2NHCH
CH2CH3
300
CDCl
(2E, 2'E): 1.32 (3H, t, COOCH CH ), 1.59 (3H, d, R (Me)CHNHCH), 3.69 (3H, s, COOMe), 4.24 (2H, q, COOCH CH ),
2
3
1
2
3
4.60 (1H, qd, R (Me)CHNHCH), 5.07 (1H, dd, R (Me)CHNHCH), 7.00 (1H, ddd, H '), 7.26 (1H, d, R (Me)CHNHCH), 7.46
1 1 5 1
(2H, dd, H , H ), 7.65 (1H, ddd, H '), 7.96 (1H, d, CHNH), 8.23 (2H, dd, H , H ), 8.33 (1H, ddd, H '), 8.41 (1H, ddd, H '),
2
6
4
3
5
3
6
11.31 (1H, d, CHNH), J
= 8.5 Hz, J
= 1.1 Hz, J
= 1.0 Hz, J
= 7.4 Hz, J
= 2.0 Hz, J
= 5.0 Hz,
H3'H4'
H3'H5'
H3'H6'
H4'H5'
H4'H6'
H5'H6'
J
J
= J
= 6.6 Hz, J
= J
= 7.1 Hz.
= 2.0 Hz, J
= 7.0 Hz, J
= 13.7 Hz, J
= 13.6 Hz,
H2H3
H5H6
H2H6
H3H5
R1(Me)CHNHCH
R1(Me)CHNHCH
R1(Me)CHNHCH
= 12.7 Hz, J
CHNH
CH2CH3
(2E,2'E) and (2Z,2'E) isomers of 25 were separated by radial chromatography (petrolether/ethyl acetate = 5:1):
25
300
(2E, 2'E): 1.31 (3H, t, COOCH CH ), 3.79 (3H, s, COOMe), 4.24 (2H, q, COOCH CH ), 6.78 (1H, br.d, R NHCH), 6.96-
2 3 2 3 1
CDCl
7.06 (4H, m, H ', 3H(Ph)), 7.29-7.35 (2H, m, 2H(Ph)), 7.66 (1H, ddd, H '), 7.92 (1H, br.d, R NHCH), 8.01 (1H, br.d,
3
5
4
1
CHNH), 8.36 (1H, ddd, H '), 8.45 (1H, ddd, H '), 11.53 (1H, br.s, CHNH), J
= 8.5 Hz, J
= 1.0 Hz, J
= 1.0 Hz,
3
6
H3'H4'
H3'H5'
H3'H6'
J
= 7.4 Hz, J
= 2.1 Hz, J
= 4.9 Hz, J
= 12.8 Hz, J
= 12.1 Hz, J
= 7.1 Hz.
H4'H5'
H4'H6'
H5'H6'
R1NHCH
CHNH CH2CH3
By addition of D O the doublet at δ = 6.78 ppm and the broad singlet at δ = 11.53 ppm disappear; the doublets at δ = 7.92
2
ppm and δ = 8.01 change into singlets.
(2Z, 2'E): 1.33 (3H, t, COOCH CH ), 3.86 (3H, s, COOMe), 4.26 (2H, q, COOCH CH ), 7.41 (1H, br.d, R NHCH), 7.63
2
3
2
3
1
(1H, ddd, H '), 8.35 (1H, ddd, H '), 8.43 (1H, ddd, H '), 9.62 (1H, br.d, R NHCH), 12.01 (1H, br.d, CHNH).
4
3
6
1
By addition of D O the doublet at δ = 9.62 ppm and the broad singlet at δ = 12.01 ppm disappear; the doublet at δ = 7.41 ppm
2
changes into singlet.
(2Z, 2'Z) and (2E, 2'Z): 1.36 (6H, t, 2x COOCH CH ), 3.76, 3.83 (6H, 2x s, 2x COOMe), 4.32 (4H, q, 2x COOCH CH ).
2
3
2
3
25 (2E, 2'E) CDCl
25 (2Z, 2'E) CDCl
1.31 (3H, t, COOCH CH ), 3.79 (3H, s, COOMe), 4.23 (2H, q, COOCH CH ), 6.83 (1H, d, R NHCH), 6.98-7.06 (4H, m, H ',
3
2 3 2 3 1 5
3H(Ph)), 7.29-7.35 (2H, m, 2H(Ph)), 7.66 (1H, ddd, H '), 7.92 (1H, d, R NHCH), 7.99 (1H, d, CHNH), 8.36 (1H, ddd, H '),
4
1
3
8.45 (1H, ddd, H '), 11.49 (1H, d, CHNH), J
= 8.5 Hz, J
= 1.0 Hz, J
= 1.0 Hz, J
= 7.4 Hz, J
= 2.1 Hz,
6
H3'H4'
H3'H5'
H3'H6'
H4'H5'
H4'H6'
J
= 4.9 Hz, J
= 13.2 Hz, J
= 12.2 Hz, J
= 7.1 Hz.
H5'H6'
R1NHCH
CHNH
CH2CH3
By addition of D O the doublets at δ = 6.83 ppm and δ = 11.49 ppm disappear; the doublets at δ = 7.92 ppm and δ = 7.99
2
change into broad singlets.
1.33 (3H, t, COOCH CH ), 3.86 (3H, s, COOMe), 4.27, (2H, q, COOCH CH ), 6.96-7.05 (4H, m, H ', 3H(Ph)), 7.30-7.35
3
2
3
2
3
5
(2H, m, 2H(Ph)), 7.41 (1H, d, R NHCH), 7.63 (1H, ddd, H '), 8.01 (1H, d, CHNH), 8.35 (1H, ddd, H '), 8.44 (1H, ddd, H '),
1
4
3
6
9.62 (1H, d, R NHCH), 12.02 (1H, d, CHNH), J
= 8.5 Hz, J
= 1.0 Hz, J
= 1.0 Hz, J
= 7.4 Hz, J
= 2.1
1
H3'H4'
H3'H5'
H3'H6'
H4'H5'
H4'H6'
Hz, J
= 4.9 Hz, J
= 12.5 Hz, J
= 12.2 Hz, J
= 7.1 Hz.
H5'H6'
R1NHCH
CHNH
CH2CH3
By addition of D O the doublets at δ = 9.62 ppm and δ = 12.02 ppm disappear; the doublets at δ = 7.41 ppm and δ = 8.01
2
change into singlets.
26
300
(2E, 2'E): 1.25 (3H, t, COOCH CH ), 3.79 (3H, s, OMe), 3.90 (3H, s, COOMe), 4.16, (2H, q, COOCH CH ), 6.95-7.11 (4H,
2
3
2
3
DMSO-d m, 4H(Ph)), 7.51 (1H, ddd, H '), 7.73 (1H, ddd, H '), 7.80 (2H, d, R NHCH, CHNH), 8.26 (1H, ddd, H '), 8.48 (1H, ddd, H '),
6
5
4
1
3
6
9.93 (1H, d, R NHCH), 12.00 (1H, d, CHNH), J
= 8.3 Hz, J
= 7.5 Hz, J
= 12.6 Hz, J
= 12.3 Hz,
1
H3'H4'
H4'H5'
R1CHNH
CHNH
J
= 7.1 Hz.
CH2CH3

Jul-Aug 2001
The Synthesis and Transformations of 2-[2-Ethoxycarbonyl-2-(2-
pyridinyl)ethenyl]amino-3-dimethylaminopropenoates
863
Table 2 (continued)
Compound MHz
Solvent
δ (tetramethylsilane)
27
28
29
300
CDCl
(2E, 2'E): 1.31 (3H, t, COOCH CH ), 3.79 (6H, s, OMe, COOMe), 4.24 (2H, q, COOCH CH ), 6.69 (1H, br.d, R NHCH),
2 3 2 3 1
6.85-7.03 (5H, m, H ', 4H(Ph)), 7.66 (1H, ddd, H '), 7.84 (1H, br.d, R NHCH), 8.00 (1H, br.d, CHNH), 8.36 (1H, ddd, H '),
3
5
4
1
3
8.44 (1H, ddd, H '), 11.42 (1H, br.s, CHNH), J
= 8.5 Hz, J
= 1.1 Hz, J
= 1.0 Hz, J
= 7.4 Hz, J
= 2.0
6
H3'H4'
H3'H5'
H3'H6'
H4'H5'
H4'H6'
Hz, J
= 5.0 Hz, J
= 13.0 Hz, J
= 12.5 Hz, J
= 7.1 Hz.
H5'H6'
R1NHCH
CHNH
CH2CH3
(2Z, 2'E): 1.33 (3H, t, COOCH CH ), 3.77, 3.84 (6H, 2x s, OMe, COOMe), 4.26 (2H, q, COOCH CH ), 7.33 (1H, d,
2
3
2
3
R NHCH), 7.63 (1H, ddd, H '), 8.34 (1H, ddd, H '), 8.43 (1H, ddd, H '), 9.54 (1H, br.d, R NHCH), 11.93 (1H, br.d, CHNH).
1
4
3
6
1
The signals for (2Z, 2'Z) and (2E, 2'Z) isomers are overlapped.
(2E, 2'E): 1.31 (3H, t, COOCH CH ), 3.78 (3H, s, COOMe), 4.24 (2H, q, COOCH CH ), 6.78 (1H, br.d, R NHCH), 6.93-
300
CDCl
2
3
2
3
1
7.06 (5H, m, H ', 4H(Ph)), 7.66 (1H, ddd, H '), 7.82 (1H, br.d, R NHCH), 7.99 (1H, br.d, CHNH), 8.34 (1H, ddd, H '), 8.43
3
5
4
1
3
1H, ddd, H '), 11.43 (1H, br.s, CHNH), J
= 8.5 Hz, J
= 1.0 Hz, J
= 0.9 Hz, J
= 7.4 Hz, J = 2.0 Hz,
6
H3'H4'
H3'H5'
H3'H6'
H4'H5'
H4'H6'
J
= 5.0 Hz, J
= 13.3 Hz, J
= 12.5 Hz, J
= 7.1 Hz.
H5'H6'
R1NHCH
CHNH
CH2CH3
(2Z, 2'E): 1.33 (3H, t, COOCH CH ), 3.85 (3H, s, COOMe), 4.26 (2H, q, COOCH CH ), 7.31 (1H, d, R NHCH), 7.63 (1H,
2
3
2
3
1
ddd, H '), 8.33 (1H, ddd, H '), 8.43 (1H, ddd, H '), 9.59 (1H, br.d, R NHCH), 12.00 (1H, br.d, CHNH).
4
3
6
1
(2Z, 2'Z) and (2E, 2'Z): 3.76, 3.83 (6H, 2x s, 2x COOMe).
(2E, 2'E): 1.22 (3H, t, COOCH CH ), 3.69 (3H, s, COOMe), 4.14 (2H, q, COOCH CH ), 7.11 (1H, ddd, H '), 7.20-7.71
300
2
3
2
3
5
DMSO-d
(3H, m, 3H (Ph)), 7.76 (1H, ddd, H '), 7.85 (1H, br.d, R NHCH), 7.89 (1H, br.d, CHNH), 8.28 (1H, ddd, H '), 8.50 (1H, ddd,
6
4
1
3
H '), 9.53 (1H, br.d, R NHCH), 11.57 (1H, br.d, CHNH), J
= 8.5 Hz, J
= 12.5 Hz, J
= 1.1 Hz, J
= 7.1 Hz.
= 1.0 Hz, J
= 7.3 Hz,
6
1
H3'H4'
H3'H5'
H3'H6'
H4'H5'
J
= 2.0 Hz, J
= 4.9 Hz, J
= 12.6 Hz, J
H4'H6'
H5'H6'
R1NHCH
CHNH CH2CH3
(2Z, 2'E): 1.25 (3H, t, COOCH CH ), 3.80 (3H, s, COOMe), 4.16 (2H, q, COOCH CH ), 7.09 (1H, ddd, H '), 7.75 (1H, ddd,
2
3
2
3
5
H '), 7.76 (1H, br.d, R NHCH), 7.99 (1H, br.d, CHNH), 8.25 (1H, ddd, H '), 8.48 (1H, ddd, H '), 9.29 (1H, br.d, R NHCH),
4
1
3
6
1
12.02 (1H, br.d, CHNH).
(2Z, 2'Z) and (2E, 2'Z): 3.68, 3.79 (6H, 2x s, 2x COOMe).
30
31
300
CDCl
(2E, 2'E): 1.34 (3H, t, COOCH CH ), 3.89 (3H, s, COOMe), 4.27 (2H, q, COOCH CH ), 6.88 (1H, ddd, H (Ph)), 7.00 (1H,
ddd, H '), 7.11 (1H, ddd, H (Ph)), 7.30 (1H, ddd, H (Ph)), 7.38 (1H, br.d, R NHCH), 7.56 (1H, dd, H (Ph)), 7.64 (1H, ddd,
5 3 4 1 6
2 3 2 3 5
3
H '), 8.03 (1H, br.d, CHNH), 8.34 (1H, ddd, H '), 8.45 (1H, ddd, H '), 10.04 (1H, br.d, R NHCH), 12.13 (1H, br.d, CHNH),
4
3
6
1
J
= 8.5 Hz, J
= 1.1 Hz, J
= 1.0 Hz, J
= 7.4 Hz, J
= 2.0 Hz, J
= 5.0 Hz, J
= 8.2 Hz, J
=
H3'H4'
H3'H5'
H3'H6'
H4'H5'
H4'H6'
H5'H6'
H3H4
H3H5
1.5 Hz, J
= 7.4 Hz, J
= 1.5 Hz, J
= 8.0 Hz, J
= 12.2 Hz, J
= 11.9 Hz, J
= 7.1 Hz.
H4H5
H4H6
H5H6
R1NHCH
CHNH
CH2CH3
(2Z, 2'E): 3.91 (3H, s, COOMe), 7.31 (1H, ddd, H (Ph)).
4
300
(2E, 2'E): 1.34 (3H, t, COOCH CH ), 3.84 (3H, s, COOMe), 4.28 (2H, q, COOCH CH ), 6.89-6.92 (1H, ddd, 1H(Ph)), 6.99
2
3
2
3
CDCl
(1H, ddd, H '), 7.12-7.23 (3H, m, 3H(Ph)), 7.32 (1H, br.d, R NHCH), 7.64 (1H, ddd, H '), 8.00 (1H, br.d, CHNH), 8.34 (1H,
3
5
1
4
ddd, H '), 8.43 (1H, ddd, H '), 9.61 (1H, br.d, R NHCH), 12.08 (1H, br.d, CHNH), J
= 8.7 Hz, J
= 1.1 Hz, J
=
3
6
1
H3'H4'
H3'H5'
H3'H6'
1.0 Hz, J
= 7.4 Hz, J
= 1.9 Hz, J
= 5.1 Hz, J
= 12.4 Hz, J
= 12.2 Hz, J
= 7.2 Hz.
H4'H5'
H4'H6'
H5'H6'
R1NHCH
CHNH CH2CH3
By addition of D O the doublets at δ = 9.61 ppm and δ = 12.08 ppm disappear; the doublets at δ = 7.32 ppm and δ = 8.00
2
ppm change into singlets.
(2Z, 2'E): 3.86 (3H, s, COOMe).
32
33
34
300
CDCl
(2E, 2'E): 1.30 (3H, t, COOCH CH ), 3.87 (3H, s, COOMe), 4.26 (2H, q, COOCH CH ), 6.99-7.06 (2H, m, H ', 1H(Ph)),
7.31-7.40 (1H, m, 1H(Ph)), 7.65 (1H, d, R NHCH), 7.67 (1H, ddd, H '), 7.78 (1H, d, CHNH), 8.22-8.32 (2H, m, 2H(Ph)),
1 4
2 3 2 3 5
3
3
3
8.40 (1H, ddd, H '), 8.47 (1H, ddd, H '), 10.23 (1H, br.d, R NHCH), 12.60 (1H, br.d, CHNH), J
= 8.5 Hz, J
= 1.1
3
6
1
H3'H4'
H3'H5'
Hz, J
= 1.1 Hz, J
= 7.4 Hz, J
= 1.9 Hz, J
= 6.0 Hz, J
= 12.2 Hz, J
= 12.6 Hz, J
= 7.2 Hz.
H3'H6'
H4'H5'
H4'H6'
H5'H6'
R1NHCH
CHNH
CH2CH3
(2Z, 2'E): 1.35 (3H, t, COOCH CH ), 3.99 (3H, s, COOMe), 4.31 (2H, q, COOCH CH ), 7.62 (1H, d, R NHCH), 7.63 (1H,
2
3
2
3
1
ddd, H '), 7.90 (1H, d, CHNH).
4
300
CDCl
(2E, 2'E): 1.30 (3H, t, COOCH CH ), 3.82 (3H, s, COOMe), 4.22 (2H, q, COOCH CH ), 7.03 (1H, ddd, H '), 7.21 (1H, br.d,
2 3 2 3 5
R NHCH), 7.29-7.32 (1H, m, 1H(Ph)), 7.45-7.50 (1H, m, 1H(Ph)), 7.67 (1H, ddd, H '), 7.83-7.88 (2H, m, 2H(Ph)), 7.86 (1H,
1 4
br.d, CHNH), 7.95 (1H, br.s, R NHCH), 8.32 (1H, ddd, H '), 8.45 (1H, ddd, H '), 11.51 (1H, br.s, CHNH), J
= 8.5 Hz,
= 12.9 Hz,
1
3
6
H3'H4'
CHNH
J
J
= 1.1 Hz, J
= 1.0 Hz, J
= 7.4 Hz, J
= 1.9 Hz, J
= 5.0 Hz, J = 12.9 Hz, J
H3'H5'
H3'H6'
H4'H5'
H4'H6'
H5'H6'
R1NHCH
= 7.2 Hz.
CH2CH3
(2Z, 2'E): 3.89 (3H, s, COOMe).
(2E, 2'E): 1.30, 1.31 (6H, 2x t, 2x COOCH CH ), 3.79 (3H, s, OMe), 4.20-4.34 (4H, m, 2x COOCH CH ), 6.69 (1H, d,
300
CDCl
2
3
2
3
R NHCH), 6.86-7.03 (5H, m, H ', 4H(Ph)), 7.66 (1H, ddd, H '), 7.81 (1H, d, R NHCH), 8.02 (1H, d, CHNH), 8.36 (1H, ddd,
1
5
4
1
H '), 8.44 (1H, ddd, H '), 11.44 (1H, d, CHNH), J
= 8.5 Hz, J
= 1.0 Hz, J
= 0.9 Hz, J
= 7.3 Hz, J
=
3
6
H3'H4'
H3'H5'
H3'H6'
H4'H5'
H4'H6'
2.0 Hz, J
= 5.0 Hz, J
= 13.4 Hz, J
= 12.3 Hz, J
= 7.1 Hz.
H5'H6'
R1NHCH
CHNH
CH2CH3
(2Z, 2'E): 1.33, 1.37 (6H, 2x t, 2x COOCH CH ), 7.31 (1H, d, R NHCH), 7.63 (1H, ddd, H '), 8.04 (1H, d, CHNH), 8.35 (1H,
2
3
1
4
ddd, H '), 8.42 (1H, ddd, H '), 9.52 (1H, d, R NHCH), 12.16 (1H, d, CHNH).
3
6
1
35
36
300
CDCl
(2E, 2'E): 1.35, 1.39 (6H, 2x t, 2x COOCH CH ), 4.28, 4.32 (4H, 2x q, 2x COOCH CH ), 6.80-6.85 (1H, m, 1H(Ph)), 6.99
2 3 2 3
(1H, ddd, H '), 7.02-7.12 (2H, m, 2H (Ph)), 7.22 (1H, d, R NHCH), 7.64 (1H, ddd, H '), 8.03 (1H, d, CHNH), 8.34 (1H, ddd,
3
5
1
4
H '), 8.42 (1H, ddd, H '), 9.57 (1H, d, R NHCH), 12.26 (1H, d, CHNH), J
= 8.5 Hz, J
= 1.1 Hz, J
= 1.0 Hz,
3
6
1
H3'H4'
H3'H5'
H3'H6'
J
= 7.4 Hz, J
= 2.0 Hz, J
= 5.0 Hz, J
= 12.2 Hz, J
= 12.2 Hz, J
= 7.1 Hz.
H4'H5'
H4'H6'
H5'H6'
R1NHCH
CHNH
CH2CH3
300
(2E, 2'E): 1.30 (3H, t, COOCH CH ), 3.80 (3H, s, COOMe), 4.22 (2H, q, COOCH CH ), 6.77 (1H, dd, H ), 7.02 (1H,
2 3 2 3 3
CDCl
ddd, H '), 7.46 (1H, d, R NHCH), 7.55 (1H, dd, H ), 7.66 (1H, ddd, H '), 7.97 (1H, br.s, R NHCH), 8.22 (1H, d, H ), 8.32
3
5
1
4
4
1
6
(1H, ddd, H '), 8.33 (1H, d, CHNH), 8.44 (1H, ddd, H '), 11.48 (1H, br.s, CHNH), J
= 8.7 Hz, J
= 0.6 Hz, J
=
3
6
H3H4
H3H6
H4H6
2.5 Hz, J
= 8.5 Hz, J
= 1.0 Hz, J
= 0.9 Hz, J
= 7.3 Hz, J
= 2.0 Hz, J
= 5.0 Hz, J
= 13.4 Hz,
H3'H4'
H3'H5'
H3'H6'
H4'H5'
H4'H6'
H5'H6'
R1NHCH
J
= 12.5 Hz, J
= 7.2 Hz.
CHNH
CH2CH3

864
L. Jukic´, S. Recˇnik, S. Golicˇ Grdadolnik, J. Svete, B. Stanovnik
Vol. 38
Table 2 (continued)
Compound MHz
Solvent
δ (tetramethylsilane)
37
300
(2E, 2'E): 1.29 (3H, t, COOCH CH ), 1.33 (3H, t, COOCH CH ), 4.22 (2H, q, COOCH CH ), 4.27 (2H, q, COOCH CH ),
2
3
2
3
2
3
2
3
CDCl
6.77 (1H, d, H ), 7.01 (1H, ddd, H '), 7.45 (1H, d, R NHCH), 7.55 (1H, dd, H ), 7.66 (1H, ddd, H '), 8.00 (1H, br.s,
3
3 5 1 4 4
R NHCH), 8.22 (1H, dd, H ), 8.29 (1H, d, CHNH), 8.32 (1H, ddd, H '), 8.44 (1H, ddd, H '), 11.56 (1H, br.s, CHNH), J
=
1
6
3
6
H3H4
8.7 Hz, J
= 0.6 Hz, J
= 2.5 Hz, J
= 8.6 Hz, J
= 1.0 Hz, J
= 0.8 Hz, J
= 7.4 Hz, J
= 1.9 Hz,
H3H6
H4H6
H3'H4'
H3'H5'
H3'H6'
H4'H5'
H4'H6'
J
= 5.0 Hz, J
= 12.7 Hz, J
= 12.6 Hz, J
= 7.2 Hz.
H5'H6'
R1NHCH
CHNH
CH2CH3
Table 3
1
H nmr (CDCl ) [a] (δ in ppm, J in Hz)
3
d
d
d
d
J
J
CHNH
R1NHCH
R1NHCH
CHNH
CHNH
R1NHCH
22 (2E, 2'E)
23 (2E, 2'E)
24 (2E, 2'E)
26 (2E, 2'E)
35 (2E, 2'E)
36 (2E, 2'E)
37 (2E, 2'E)
30 [b] (2E, 2'E)
(2Z, 2'E)
31 [b] (2E, 2'E)
(2Z, 2'E)
32 [b] (2E, 2'E)
(2Z, 2'E)
33 [b] (2E, 2'E)
(2Z, 2'E)
34 (2E, 2'E)
(2Z, 2'E)
25 [b] (2E, 2'E)
(2Z, 2'E)
(2Z, 2'Z) and (2E, 2'Z)
27 [b] (2E, 2'E)
(2Z, 2'E)
(2Z, 2'Z) and (2E, 2'Z)
28 [b] (2E, 2'E)
(2Z, 2'E)
(2Z, 2'Z) and (2E, 2'Z)
29 [b] (2E, 2'E)
(2Z, 2'E)
7.44
7.44
7.26
7.80
7.22
7.46
7.45
7.38
7.38
7.32
7.32
7.65
7.62
7.21
7.21
7.81
7.31
7.92
7.41,
7.41, 7.92
7.84
7.33
2X 7.84
7.82
7.31
2X 7.82
7.85
7.76
5.09
5.03
5.07
9.93
9.57
7.97
8.00
10.04
10.04
9.61
9.61
10.23
10.23
7.95
7.95
6.69
9.52
6.78
9.62
6.78, 9.62
6.69
9.54
6.69, 9.54
6.78
9.59
6.78, 9.59
9.53
9.29
7.95
7.93
7.96
7.80
8.03
8.33
8.29
8.03
8.03
8.00
8.00
7.78
7.90
7.86
7.86
8.02
8.04
8.01
8.01
2X 8.01
8.00
8.00
2X 8.00
7.99
7.99
2X 7.99
7.89
7.99
11.27
11.28
11.31
12.00
12.26
11.48
11.56
12.13
12.13
12.08
12.08
12.60
12.60
11.51
11.51
11.44
12.16
13.8
13.9
13.6
12.6
12.2
13.4
12.7
12.2
12.2
12.4
12.4
12.2
12.2
12.9
12.9
13.4
13.4
12.8
12.8
12.8
13.0
13.0
13.0
13.3
13.3
13.3
12.6
12.6
12.6
9.0
-
12.7
12.3
12.2
12.5
12.6
11.9
11.9
12.2
12.2
12.6
12.6
12.9
12.9
12.3
12.3
12.1
12.1
12.1
12.5
12.5
12.5
12.5
12.5
12.5
12.5
12.5
12.5
11.53
12.01
11.53, 12.01
11.42
11.93
11.42, 11.93
11.43
12.00
11.43, 12.00
11.57
12.02
11.57, 12.02
(2Z, 2'Z) and (2E, 2'Z)
7.76, 7.85
9.29, 9.53
7.89, 7.99
[a] Spectra of compounds 26 and 29 were obtained in dimethyl sulfoxide-d as solvent. [b] The similar chemical shifts and coupling
6
1
constants for R NHCH, R NHCH, CHNH, and CHNH for (2E, 2'E) and (2Z, 2'E) isomers in H nmr spectra of compounds 30-33
and for some isomers in H nmr spectra of compounds 25, 27-29 result in broad singlets and broad doublets due to overlapping.
1
1
1
(HMBC) experiments. The HMBC nmr experiment of com-
pound 5 in deuteriochloroform solution at room temperature
shows that the compound exists in one isomeric form. The
orientation around the C=C double bond was deduced from
dimethylaminomethylene group, a doublet at δ = 7.90-7.93
ppm for CHNH and δ = 11.52-11.58 ppm for CHNH with
the coupling constant J
= 12.5-12.6 Hz, thus indicating
CHNH
3 13
1
the coupling constant J
= 4.5 Hz, which indicates
C=O, H
1
the (E) orientation (Figure 1). The H nmr chemical shifts and
coupling constants for compound 5 [δ(CHNH) = 7.92 ppm,
δ(CHNH) = 11.02 ppm, J
= 12.8 Hz] are of similar val-
CH-NH
ues as those for compound 6 [δ(CHNH) = 7.93 ppm,
δ(CHNH) = 11.02 ppm, J
= 12.4 Hz].
CH-NH
1
The H nmr spectra of compounds 7 and 8 in deuterio-
chloroform exhibit besides the signals characteristic for
pyridine ring, ethyl and methyl groups in esters, and

Jul-Aug 2001
The Synthesis and Transformations of 2-[2-Ethoxycarbonyl-2-(2-
pyridinyl)ethenyl]amino-3-dimethylaminopropenoates
865
Table 4
13
C nmr Data
Compound
MHz
Solvent
δ (tetramethylsilane)
5
75.5
14.70 (COOCH CH ), 50.16 (COOCH ), 52.51 (CH NH), 59.48 (COOCH CH ), 97.04, 118.73, 122.34,
2 3 3 2 2 3
CDCl
75.5
CDCl
75.5
CDCl
75.5
135.95, 146.19, 153.21, 157.58, 167.92, 170.23.
15.00 (COOCH CH ), 43.12 (N(CH ) ), 51.75 (COOCH ), 59.64 (COOCH CH ), 96.66, 101.11, 118.75,
3
3
3
7
2
3
3 2
3
2
3
122.51, 136.16, 144.81, 146.42, 155.66, 158.28, 168.46, 168.55.
14.96, 15.00 (2x COOCH CH ), 43.07 (N(CH ) ), 59.61, 60.36 (2x COOCH CH ), 96.49, 101.50, 118.72,
8
2
3
3 2
2
3
122.47, 136.16, 144.27, 146.40, 155.58, 158.34, 167.98, 168.49.
15.05 (COOCH CH ), 52.20 (COOCH ), 56.52 (OMe), 59.37 (COOCH CH ), 96.15, 106.11, 111.83, 113.43,
26
2
3
3
2
3
DMSO-d
75.5
119.18, 121.69, 121.99, 122.76, 129.91, 136.61, 136.94, 146.89, 147.80, 151.48, 157.62, 166.84, 167.59.
15.01, 15.05 (2X COOCH CH ), 52.01, 52.21 (2X COOCH ), 59.41, 59.66 (2X COOCH CH ), 96.22, 97.37, 106.86,
6
29 [a]
2
3
3
2
3
DMSO-d
107.33, 116.57, 116.66, 116.95, 117.04, 117.75, 117.82, 118.05, 118.16, 119.20, 119.36, 120.39, 120.55, 120.64,
120.80, 122.02, 122.11, 135.03, 136.61, 136.68, 137.04, 138.81, 139.40, 139.43, 146.86, 147.01, 148.84, 151.20,
151.62, 154.07, 154.81, 157.59, 157.68, 166.16, 166.31, 167.47, 167.60.
6
13
[a] The assigments of two major isomers in C nmr spectrum are based on the signals of aliphatic groups. The assigments of other signals were not pos-
13 19
sible due to overlapping and C- F couplings.
that the orientation of protons in NHCH structural element
is trans (antiperiplanar). The orientation around the C=C
double bonds was determined on the basis of HMBC nmr
experiment for compound 7, indicating that compound
exists in one isomeric form. Both coupling constants,
3 13
1
J
are 3 Hz and 4 Hz, respectively, indicating that the
CO, H
orientation around C(2)=C(3) is (Z), while the orientation
around the C(2')=C(3') is (E). (Figure 2).
3 13
1
K) indicates (2E,2'E) orientation ( J
= 9 Hz for
= 4 Hz for
CO, H
1
1
13
3 13
1
H-C(3)=C(2)- COOMe, and
J
CO, H
13
H-C(3')=C(2')- COOEt) and (2Z, 2'E) orientation
3 13
1
1
13
( J
= 4 Hz for H-C(3)=C(2)- COOMe, and
CO, H
3 13
1
1
13
J
= 4 Hz for H-C(3')=C(2')- COOEt) for two
CO, H
major isomers, respectively. (Figure 4). The determination
of orientations around the double bonds for two minor iso-
mers was not possible due to low ratios and overlapping
with the signals of major isomers.
1
The H nmr spectra of crude compounds 22-37 [24]
exhibit one, two or four sets of signals, indicating that
these compounds exist in one, two or four isomeric forms.
The ratio of isomers was determined on the basis of peaks
for methyl and ethyl groups in esters, except for com-
pounds 27 and 34, due to overlapping of signals.
Compound 26 exists as a single isomer. The HMBC nmr
experiment in dimethyl sulfoxide-d (at 302 K), shows on
6
3 13
1
the basis of the coupling constants J
= 9 Hz for
CO, H
1
13
3 13
1
1
H-C(3)=C(2)- COOMe and J
= 4 Hz for H-
CO, H
13
C(3')=C(2')- COOEt, that the compound exists in the
(2E,2'E) form. (Figure 3). In H nmr spectrum, compound
1
29 shows four sets of signals in the ratio of 13:9:2:1. The
HMBC nmr experiment in dimethyl sulfoxide-d (at 302
6

866
L. Jukic´, S. Recˇnik, S. Golicˇ Grdadolnik, J. Svete, B. Stanovnik
Vol. 38
General Procedure for the Preparation of Alkyl (Z)-2-[(E)-2-
Ethoxycarbonyl-2-(2-pyridinyl)ethenyl]amino-3-dimethy-
laminopropenoates 7, 8.
The orientation around the double bonds for all other
compounds were determined on the basis of analogous
chemical shifts for CHNH and CHNH, and J
cou-
CH-NH
1
pling constants in H nmr spectra. In all cases the orienta-
tion in major isomer is (E) for C(2)=C(3) and (E) for
C(2')=C(3') and in the second major isomer (or in the
minor isomer for compounds which exist in two isomeric
forms, respectively) is (Z) around the C(2)=C(3) and (E)
around the C(2')=C(3') double bonds. Assignments of sig-
nals for the two minor isomers, (2Z, 2'Z) and (2E, 2'Z), for
those compounds, which exist as four isomeric forms,
were not possible. (Table 5).
To compound 5 or 6 (10 mmol) suspended in dry toluene (10
ml), Bredereck's reagent (20 mmol) was added and the mixture
was heated under reflux for several hours. The volatile com-
pounds were evaporated in vacuo and the mixture of ethyl
acetate (5 ml)/n-heptane (15 ml) was added. The precipitate
was collected by filtration and washed with ether. The follow-
ing compounds were prepared in this manner: methyl (Z)-2-
[(E)-2-ethoxycarbonyl-2-(2-pyridinyl)ethenyl]amino-3-
dimethylaminopropenoate (7) and ethyl (Z)-2-[(E)-2-ethoxy-
carbonyl-2-(2-pyridinyl)ethenyl]amino-3-dimethylamino-
Table 5
HMBC nmr Data
Compound
Solvent
Temp.
3 13
1
5
7
CDCl
302 K
CDCl
302 K
DMSO-d
302 K
DMSO-d
302 K
One isomer (E): J
= 4.5 Hz
3
CO, H
3 13
1
1
13
One isomer (2Z, 2'E): J
= 3 Hz for H-C(3)=C(2)- COOMe
= 4 Hz for H-C(3')=C(2')- COOEt
= 9 Hz for H-C(3)=C(2)- COOMe
= 4 Hz for H-C(3')=C(2')- COOEt
3
CO, H
3 13
1
1
13
J
CO, H
3 13
1
1
13
26
29
One isomer (2E, 2'E): J
6
6
CO, H
3 13
1
1
13
J
CO, H
Four isomers (13:9:2:1)
Major isomer (2E, 2'E): J
3 13
1
1
13
= 9 Hz for H-C(3)=C(2)- COOMe
= 4 Hz for H-C(3')=C(2')- COOEt
= 4 Hz for H-C(3)=C(2)- COOMe
= 4 Hz for H-C(3')=C(2')- COOEt
CO, H
3 13
1
1
13
J
CO, H
3 13
1
1
13
Minor isomer (2Z,2'E): J
CO, H
3 13
1
1
13
J
CO, H
propenoate (8). Experimental and analytical data are given in
Tables 1, 2, 4, and 5.
EXPERIMENTAL
1
Melting points were taken on a Kofler micro hot stage. The H
nmr spectra were obtained on a Bruker Avance DPX 300 (300
General Procedure for the Preparation of β-Alkylamino-α,β-
didehydro-α-amino Acid Derivatives 22-24.
MHz) spectrometer in such solvent as dimethyl sulfoxide-d and
6
To compound 7 (0.5 mmol, 160 mg) the corresponding
aliphatic amine 9-11 (0.5 mmol) and acetic acid (2 ml) were
added and stirred at room temperature for 24 hours. The
volatile compounds were evaporated in vacuo, the appropriate
solvent (3 ml) was added and the precipitate was collected by
filtration.
deuteriochloroform with tetramethylsilane as internal standard.
The elemental analyses for C, H and N were obtained on a
Perkin-Elmer CHN Analyser 2400.
General Procedure for the Preparation of Alkyl (E)-N-[2-
Ethoxycarbonyl-2-(2-pyridinyl)ethenyl]glycinates 5, 6.
Methyl (E)-2-[(E)-2-Ethoxycarbonyl-2-(2-pyridinyl)ethenyl]−
amino-3-benzylaminopropenoate (22).
The mixture of ethyl 2-pyridinylacetate (1) (20 mmol, 3 ml)
and Bredereck's reagent (25 mmol, 5 ml) was stirred in the oil
bath at 85 °C in an argon atmosphere for 1.5 hours. Then ethanol
(10 ml) was added and the volatile compounds were evaporated
in vacuo. The obtained oily residue, ethyl 3-dimethylamino-2-(2-
pyridinyl)propenoate (2), was without further purification dis-
solved in ethanol (25 ml), glycine alkyl ester hydrochloride 3 or 4
(20 mmol) was added, and the mixture was heated under reflux
for 1.5 hours. The volatile compounds were evaporated in vacuo
and water (30 ml) was added. The precipitate, which had been
formed in refrigerator, was collected by filtration and washed
with ether (5 ml). The following compounds were prepared in
this manner: methyl (E)-N-[2-ethoxycarbonyl-2-(2-pyridinyl)-
ethenyl]glycinate (5) from glycine methyl ester hydrochloride (3)
(20 mmol, 2.5 g) and ethyl (E)-N-[2-ethoxycarbonyl-2-(2-
pyridinyl)ethenyl]glycinate (6) from glycine ethyl ester
hydrochloride (4) (20 mmol, 2.8 g). Experimental and analytical
data are given in Tables 1, 2, and 5.
This compound was prepared from bezylamine hydrochloride
(9) (0.5 mmol, 54 mg). The mixture of ethanol (1 ml) and water
(1 ml) was used for crystallization. Experimental and analytical
data are given in Tables 1,2 , and 3.
Methyl (E)-2-[(E)-2-Ethoxycarbonyl-2-(2-pyridinyl)ethenyl]−
amino-3-(4-methoxybenzyl)aminopropenoate (23).
This compound was prepared from 4-methoxybezylamine (10)
(0.5 mmol, 63 mg). The mixture of ethanol (1 ml) and water (1
ml) was used for crystallization. Experimental and analytical data
are given in Tables 1, 2, and 3.
Methyl (E)-2-[(E)-2-Ethoxycarbonyl-2-(2-pyridinyl)ethenyl]−
amino-3-(4-nitro-α-methylbenzyl)aminopropenoate (24).
This compound was prepared from 4-nitro-α-methylbezyl-
amine hydrochloride (11) (0.5 mmol, 101 mg). Acetone (2 ml)

Jul-Aug 2001
The Synthesis and Transformations of 2-[2-Ethoxycarbonyl-2-(2-
pyridinyl)ethenyl]amino-3-dimethylaminopropenoates
867
was used for crystallization. Experimental and analytical data are
given in Tables 1, 2, and 3.
6:1 ratio. Methanol (2 ml) was used for crystallization.
Experimental and analytical data are given in Tables 1, 2, and 3.
Methyl (E)-2-[(E)-2-[2-Ethoxycarbonyl-2-(2-pyridinyl)-
ethenyl]amino-3-(3-bromophenyl)aminopropenoate (31) and
(Z)-2-[(E)- Isomer.
General Procedure for the Preparation of β-Arylamino-α,β-dide-
hydro-α-amino Acid Derivatives 25-35.
To compound 7 (0.5 mmol, 160 mg) or 8 (0.5 mmol, 167 mg)
the corresponding aromatic amine 12-20 (0.5 mmol) and acetic
acid (2 ml) were added and stirred at room temperature for a few
minutes to 24 hours. The volatile compounds were evaporated in
vacuo, the appropriate solvent (3 ml) was added and the precipi-
tate was collected by filtration.
This compound was prepared from compound 7 (0.5 mmol,
160 mg) and 3-bromoaniline (18) (0.5 mmol, 83 mg), 24 hours, in
7:1 ratio. Methanol (2 ml) was used for crystallization.
Experimental and analytical data are given in Tables 1, 2, and 3.
Methyl (E)-2-[(E)-2-Ethoxycarbonyl-2-(2-pyridinyl)ethenyl]−
amino-3-(2-nitrophenyl)aminopropenoate (32) and (Z)-2-[(E)-
Isomer.
Methyl (E)-2-[(E)-2-Ethoxycarbonyl-2-(2-pyridinyl)ethenyl]−
amino-3-phenylaminopropenoate (25) and (Z)-2-[(E)-, (Z)-2-
[(Z)-, and (E)-2-[(Z)- Isomers.
This compound was prepared from compound 7 (0.5 mmol,
160 mg) and 2-nitroaniline (19) (0.5 mmol, 70 mg), 10 minutes,
in 10:1 ratio. Methanol (2 ml) was used for crystallization.
Experimental and analytical data are given in Tables 1, 2, and 3.
This compound was prepared from compound 7 (0.5 mmol,
160 mg) and alanine (12) (0.5 mmol, 47 mg), 24 hours, in
11:9:2:1 ratio. The mixture of methanol (1 ml) and water (1 ml)
was used for crystallization. Two isomers, (E)-2-[(E)- and (Z)-2-
[(E)-, were separated with radial chromatography (petrol-
ether/ethyl acetate = 5:1). Experimental and analytical data are
given in Tables 1, 2, and 3.
Methyl (E)-2-[(E)-2-Ethoxycarbonyl-2-(2-pyridinyl)ethenyl]−
amino-3-(3-nitrophenyl)aminopropenoate (33) and (Z)-2-[(E)-
Isomer.
This compound was prepared from compound 7 (0.5 mmol,
160 mg) and 3-nitroaniline (20) (0.5 mmol, 70 mg), 24 hours, in
8:1 ratio. Methanol (2 ml) was used for crystallization.
Experimental and analytical data are given in Tables 1, 2, and 3.
Methyl (E)-2-[(E)-2-Ethoxycarbonyl-2-(2-pyridinyl)ethenyl]−
amino-3-(2-methoxyphenyl)aminopropenoate (26).
This compound was prepared from compound 7 (0.5 mmol,
160 mg) and 2-methoxyaniline (13) (0.5 mmol, 62 mg), 24 hours.
The mixture of methanol (1 ml) and water (1 ml) was used for
crystallization. Experimental and analytical data are given in
Tables 1, 2, 3, and 5.
Ethyl (E)-2-[(E)-2-Ethoxycarbonyl-2-(2-pyridinyl)ethenyl]−
amino-3-(4-methpxyphenyl)aminopropenoate (34) and (Z)-2-
[(E)- Isomer.
This compound was prepared from compound 8 (0.5 mmol, 167
mg) and 4-methoxyaniline (14) (0.5 mmol, 61 mg), 24 hours. The
ratio was not defined. Ethanol (2 ml) was used for crystallization.
Experimental and analytical data are given in Tables 1, 2, and 3.
Methyl (E)-2-[(E)-2-Ethoxycarbonyl-2-(2-pyridinyl)ethenyl]−
amino-3-(4-methoxyphenyl)aminopropenoate (27) and (Z)-2-
[(E)-, (Z)-2-[(Z)-, and (E)-2-[(Z)- Isomers.
This compound was prepared from compound 7 (0.5 mmol, 160
mg) and 4-methoxyaniline (14) (0.5 mmol, 61 mg), 24 hours. The
ratio was not defined. Methanol (2 ml) was used for crystallization.
Experimental and analytical data are given in Tables 1, 2, and 3.
Ethyl (E)-2-[(E)-2-Ethoxycarbonyl-2-(2-pyridinyl)ethenyl]−
amino-3-(4-fluoro-3-chlorophenyl)aminopropenoate (35).
This compound was prepared from compound 8 (0.5 mmol,
167 mg) and 4-fluoro-3-chloroaniline (16) (0.5 mmol, 74 mg), 24
hours. Ethanol (2 ml) was used for crystallization. Experimental
and analytical data are given in Tables 1, 2, and 3.
Methyl (E)-2-[(E)-2-Ethoxycarbonyl-2-(2-pyridinyl)ethenyl]−
amino-3-(4-flourophenyl)aminopropenoate (28) and (Z)-2-[(E)-,
(Z)-2-[(Z)-, and (E)-2-[(Z)- Isomers.
The Preparation of β-Heteroarylamino-α,β-didehydro-α-amino
Acid Derivatives 36, 37.
This compound was prepared from compound 7 (0.5 mmol,
160 mg) and 4-fluoroaniline (15) (0.5 mmol, 56 mg), 24 hours, in
11:6:1:1 ratio. Methanol (2 ml) was used for crystallization.
Experimental and analytical data are given in Tables 1, 2, and 3.
Methyl (E)-2-[(E)-2-Ethoxycarbonyl-2-(2-pyridinyl)ethenyl]−
amino-3-(5-chloro-2-pyridinyl)aminopropenoate (36).
To compound 7 (0.5 mmol, 160 mg) 2-amino-5-chloropyridine
(21) (0.5 mmol, 64 mg) and acetic acid (2 ml) were added and
stirred at room temperature for 4 days. The volatile compounds
were evaporated in vacuo and ethanol (2 ml) was added. The pre-
cipitate was collected by filtration and washed with ethanol.
Experimental and analytical data are given in Tables 1, 2, and 3.
Methyl (E)-2-[(E)-2-Ethoxycarbonyl-2-(2-pyridinyl)ethenyl]−
amino-3-(3-chloro-4-flourophenyl)aminopropenoate (29) and
(Z)-2-[(E)-, (Z)-2-[(Z)-, and (E)-2-[(Z)- Isomers.
This compound was prepared from compound 7 (0.5 mmol,
160 mg) and 3-chloro-4-fluoroaniline (16) (0.5 mmol, 74 mg),
24 hours, in 13:9:2:1 ratio. Methanol (2 ml) was used for crys-
tallization. Experimental and analytical data are given in Tables
1,2, 3, and 5.
Ethyl (E)-2-[(E)-2-Ethoxycarbonyl-2-(2-pyridinyl)ethenyl]−
amino-3-(5-chloro-2-pyridinyl)aminopropenoate (37).
To compound 8 (0.5 mmol, 167 mg) 2-amino-5-chloropyridine
(21) (0.5 mmol, 64 mg) and acetic acid (2 ml) were added and
stirred at room temperature for 24 hours. The volatile compounds
were evaporated in vacuo and ethanol (2 ml) was added. The pre-
cipitate was collected by filtration and washed with ethanol.
Experimental and analytical data are given in Tables 1, 2, and 3.
Methyl (E)-2-[(E)-2-[2-Ethoxycarbonyl-2-(2-pyridinyl)-
ethenyl]amino-3-(2-bromophenyl)aminopropenoate (30) and
(Z)-2-[(E)- Isomer.
This compound was prepared from compound 7 (0.5 mmol,
160 mg) and 2-bromoaniline (17) (0.5 mmol, 83 mg), 24 hours, in

868
L. Jukic´, S. Recˇnik, S. Golicˇ Grdadolnik, J. Svete, B. Stanovnik
Vol. 38
[13] L. Selicˇ and B. Stanovnik, Synthesis, 1999, 479.
[14] L. Selicˇ and B. Stanovnik, Helv. Chim. Acta, 81, 1634
(1998).
Acknowledgment.
The financial support by the Ministry of Science and
Technology of Slovenia is gratefully acknowledged.
[15] L. Selicˇ, R. Jaksˇe, K. Lampicˇ, L. Golicˇ, S. Golicˇ
Grdadolnik, and B. Stanovnik, Helv. Chim. Acta, 83, 2802 (2000).
[16] L. Jukic´, J. Svete, A. Golobicˇ, L. Golicˇ, and B. Stanovnik,
Heterocycles, 53, 805 (2000).
REFERENCES AND NOTES
ˇ
[17] M. Skof, J. Svete, B. Stanovnik, L. Golicˇ, S. Golicˇ
[1] L. Selicˇ, S. Golicˇ Grdadolnik, and B. Stanovnik, Helv.
Chim. Acta, 80, 2418 (1997).
Grdadolnik, and L. Selicˇ, Helv. Chim. Acta, 81, 2332 (1998).
ˇ
[18] M. Skof, J. Svete, M. Kmeticˇ, S. Golicˇ Grdadolnik, and B.
[2] R. Toplak, L. Selicˇ, G. Sorsˇak, and B. Stanovnik,
Heterocycles, 45, 555 (1997).
Stanovnik, Eur. J. Org. Chem., 1999, 1581.
ˇ
[19] M. Skof, J. Svete, and B. Stanovnik, Heterocycles, 51,
[3] L. Pizzioli, B. Ornik, J. Svete, and B. Stanovnik, Helv.
Chim. Acta, 81, 231 (1998).
1051 (1999).
ˇ
[20] M.Skof, J. Svete, and B. Stanovnik, Heterocycles, 52, 845
[4] J. Smodisˇ and B. Stanovnik, Tetrahedron, 54, 9799 (1998).
[5] R. Toplak, J. Svete, B. Stanovnik, and S. Golicˇ
Grdadolnik, J. Heterocyclic Chem., 36, 225 (1999).
[6] R. Toplak, J. Svete, S. Golicˇ Grdadolnik, and B.
Stanovnik, Collect. Czech. Chem. Commun., 64, 177 (1999).
[7] L. Selicˇ, S. Golicˇ Grdadolnik, and B. Stanovnik,
Heterocycles, 49, 133 (1998).
[8] R. Toplak, M. Zucchiati, S. Golicˇ Grdadolnik, and B.
Stanovnik, Heterocycles, 50, 853 (1999).
[9] U. Bratusˇek, A. Hvala, and B. Stanovnik, J. Heterocyclic
Chem., 35, 1281 (1998).
[10] S. Recˇnik, R. Toplak, J. Svete, L. Pizzioli, and B.
Stanovnik, J. Heterocyclic Chem., 37, 783 (2000).
[11] L. Selicˇ and B. Stanovnik, J. Heterocyclic Chem., 35, 1527
(1999).
[12] M. Malesˇicˇ, A. Krbavcˇicˇ, A. Golobicˇ, L. Golicˇ, and B.
Stanovnik, J. Heterocyclic Chem., 34, 1757 (1997).
(2000).
ˇ
[21] M.Skof, J. Svete, and B. Stanovnik, Heterocycles, 53, 339
(2000).
[22] M. Skof, J. Svete, and B. Stanovnik, J. Heterocyclic
Chem., 37, 703 (2000).
ˇ
[23] For reviews see: [a] B. Stanovnik, J. Heterocyclic Chem.,
36, 1581 (1999); [b] B. Stanovnik and J. Svete, Synlett, 2000, 1077;
[c] B. Stanovnik and J. Svete, "Alkyl 3-(Dimethylamino)propenoates
and Related Compounds as Useful Building Blocks in the Synthesis
of Heterocyclic Systems – Approaches Towards the Synthesis of
Natural Products and their Close Analogs" in "Targets in
Heterocyclic Systems. Chemistry and Properties", O. A. Attanasi, D.
Spinelli, eds., Vol. 4, Reviews and Accounts on Heterocyclic
Chemistry, Italian Society of Chemistry, Rome 2000, pp. 105-137.
[24] The samples of crude products 22-37, isolated from the
reaction mixtures were used without further purification for determi-
1
nation of isomer ratios by H nmr techniques.